Chiral vicinal aminoalcohols are important intermediates in the synthesis of various pharmaceutical products and product candidates, yet the preparation of these compounds remains a significant synthetic challenge to chemists. Vicinal aminoalcohols which contain chiral centers at either the carbon bearing the amino group, the carbon bearing the hydroxy group, or at both carbons are the subject of the present invention. Gaining control over the stereochemistry of these chiral centers at reasonable cost is the key to the successful production of these important chemical compounds.
One example of an important chiral vicinal aminoalcohol is found in SCH 56592, described in Tetrahedron Letters 37, 5657 (1996) and references therein, hereby incorporated by reference. SCH 56592 is a potent antifungal compound. A key component in the synthesis of SCH 56592 is the chiral vicinal aminoalcohol moiety (3S,4S)-3-amino-4-hydroxypentane. No efficient and cost effective route for its synthesis has been described.
Another example of an important chiral vicinal aminoalcohol is found in the drug Crixivan, an HIV-protease inhibitor produced by Merck & Co. This compound is one of the most potent inhibitors of the AIDS virus yet discovered. A key intermediate in its synthesis is the chiral vicinal aminoalcohol (1S,2R)-1-amino-2-indanol (1997 Physicians' Desk Reference, Medical Economics Company, Montvale, N.J., pp. 1670-1673).
There are a number of additional examples of important molecules which contain chiral aminoalcohols, including ephedrine, pseudoephedrine, norephedrine, pseudo-norephedrine, epinephrine, norepinephrine, isoserinol, isoleucinol, histidinol, 2-aminocyclopentanol, 2-aminocyclohexanol, phenylglycinol, and many others. Methods for the production of compounds which contain chiral aminoalcohol functionality tend to be specific for a given molecule or small group of related molecules. For example, several routes exist for the production of ephedrine (see, for example Fodor, Recent Develop. Chem. Nat. Carbon Compounds 1, 15-160 (1965). However, these methods are not broadly generalizable to many other chiral vicinal aminoalcohols. The enzyme serine hydroxymethyltransferase can catalyze the production of certain chiral vicinal aminoalcohols such as threonine and phenylserine, but only with severe structural limitations; there is an absolute requirement for glycine as a substrate, limiting carbon-1 to being only a carboxyl group. In addition, only certain aldehydes are accepted as substrates to condense with glycine. Furthermore, a mixture of stereoisomers is invariably obtained, making the production and recovery of highly pure chiral vicinal aminoalcohols difficult. (See C. Bull et al. in Biocatalytic Production of Amino Acids and Derivatives, D. Rozzell and F. Wagner, Eds., Hanser Publishers, Munich, (1992) pp. 255-256.) Often, classical resolution procedures are used due to the absence of any better method, resulting in the loss of 50% or more of the starting material (see, for example Tullar, J. Am. Chem. Soc. 70, 2067 (1948) which describes the resolution of D,L-epinephrine). A general method for the production of molecules of high optical purity incorporating a chiral vicinal aminoalcohol would facilitate the production of this important class of pharmaceutical intermediates and would be greatly desired.